제현수 (Duke NUS Graduate Medical School, National University of Singapore) | 한빛사논문 > 한빛사

한빛사논문

조회2,926

Duke NUS Graduate Medical School, National University of Singapore

CV File 124 kb

Biol. Psychiatry, Available online 28 August 2015 | doi:10.1016/j.biopsych.2015.08.019 Regulation of BDNF exocytosis and GABAergic interneuron synapse by the schizophrenia susceptibility gene dysbindin-1

Abstract

Qiang Yuan^{a, 1}, Feng Yang^{b, 1}, Yixin Xiao^a, Shawn Tan^a, Nilofer Husain^a, Ming Ren^b, Zhonghua Hu^b, Keri Martinowich^b, Julia S. Ng^a, Paul J. Kim^a, Weiping Han^c, Koh-ichi Nagata^d, Daniel R. Weinberger^b. Shawn Je^{a, e, *}

^a Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke NUS Graduate Medical School, 8 College Road, 169857, Singapore

^b Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA

^c Singapore Bioimaging Consortium, Helios, 11 Biopolis way, 138667, Singapore

^d Institute for Developmental Research, Aichi Human Service Center, Kasugai, 480-0392, Japan

^e Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore

^*Correspondence to: H. Shawn Je, Ph.D., Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857.

¹ These authors contributed equally to this work.

Abstract

Background

Genetic variations in dystrobrevin binding protein-1 (DTNBP1 or dysbindin-1) have been implicated as risk factors in the pathogenesis of schizophrenia. The encoded protein dysbindin-1 functions in the regulation of synaptic activity and synapse development. Intriguingly, a loss of function mutation in Dtnbp1 in mice disrupted both glutamatergic and GABAergic transmission in the cerebral cortex; pyramidal neurons displayed enhanced excitability due to reductions in inhibitory synaptic inputs. However, the mechanism by which reduced dysbindin-1 activity causes inhibitory synaptic deficits remains unknown.

Methods

We investigated the role of dysbindin-1 in the exocytosis of brain-derived neurotrophic factor (BDNF) from cortical excitatory neurons, organotypic brain slices, and acute slices from dysbindin-1 mutant mice and determined how this change in BDNF exocytosis trans-synaptically affected the number of inhibitory synapses formed on excitatory neurons, via whole-cell recordings, immunohistochemistry, and live-cell imaging using total internal reflection fluorescence microscopy (TIRFM).

Results

A decrease in dysbindin-1 reduces the exocytosis of BDNF from cortical excitatory neurons, and this reduction in BDNF exocytosis trans-synaptically resulted in reduced inhibitory synapse numbers formed on excitatory neurons. Furthermore, application of exogenous BDNF rescued the inhibitory synaptic deficits caused by the reduced dysbindin-1 level in both cultured cortical neurons and slice cultures.

Conclusion

Taken together, our results demonstrate that these two genes linked to risk for schizophrenia (BDNF and dysbindin-1) function together to regulate interneuron development and cortical network activity. This evidence supports the investigation of the association between dysbindin-1 and BDNF in humans with schizophrenia.

Key Words : Dysbindin-1; DTNBP1; brain-derived neurotrophic factor (BDNF); gamma-aminobutyric acid (GABA); interneuron synapse; schizophrenia; exocytosis

논문정보

형식Research article
게재일2015년 08월 (BRIC 등록일 2015-09-10)
연구진국외 연구진
분야 의약학 > 신경의학

댓글 작성 로그인

CV 열람하기

연락처 보기